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Fulltext Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

Khaidizar FD, Bessho Y, Nakahata Y

Int J Mol Sci, 2021 Apr 02;22(7).
PMID: 33918226 DOI: 10.3390/ijms22073709

Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.
Intron retention is among six unreported AGL mutations identified in Malaysian GSD III patients

Abdullah IS, Teh SH, Khaidizar FD, Ngu LH, Keng WT, Yap S, et al.

Genes Genomics, 2019 08;41(8):885-893.
PMID: 31028654 DOI: 10.1007/s13258-019-00815-9

BACKGROUND: Glycogen storage disease type III is an autosomal recessive disorder that is caused by deficiencies of the glycogen debranching enzyme. Mutations within the AGL gene have been found to be heterogeneous, with some common mutations being reported in certain populations. The mutation spectrum of AGL gene in the multi-ethnic Malaysian population is still unknown.
OBJECTIVE: The present study seeks to determine the mutation spectrum of the AGL gene in Malaysian population.
METHODS: A total of eleven patients (eight Malay, two Chinese and one Bajau) were investigated. Genomic DNA was extracted and subsequently the AGL gene was amplified using specific primers and sequenced. Mutations found were screened in 150 healthy control samples either by restriction enzyme digestion assay or TaqMan® SNP Genotyping assay.
RESULTS: We identified six unreported mutations (c.1423+1G>T, c.2914_2915delAA, c.3814_3815delAG, c.4333T>G, c.4490G>A, c.4531_4534delTGTC) along with three previously reported mutations (c.99C>T, c.1783C>T, c.2681+1G>A). One of the six unreported mutation causes abnormal splicing and results in retention of intron 12 of the mature transcript, while another is a termination read-through. One of the reported mutation c.2681+1G>A was recurrently found in the Malay patients (n = 7 alleles; 31.8%).
CONCLUSION: The mutation spectrum of the AGL gene in Malaysian patients has shown considerable heterogeneity, and all unreported mutations were absent in all 150 healthy control samples tested.
Fulltext Over-expression of Nicotinamide phosphoribosyltransferase in mouse cells confers protective effect against oxidative and ER stress-induced premature senescence

Nuriliani A, Nakahata Y, Ahmed R, Khaidizar FD, Matsui T, Bessho Y

Genes Cells, 2020 Aug;25(8):593-602.
PMID: 32533606 DOI: 10.1111/gtc.12794

A main feature of aged organisms is the accumulation of senescent cells. Accumulated senescent cells, especially stress-induced premature senescent cells, in aged organisms lead to the decline of the regenerative potential and function of tissues. We recently reported that the over-expression of NAMPT, which is the rate-limiting enzyme in mammalian NAD+ salvage pathway, delays replicative senescence in vitro. However, whether Nampt-overexpressing cells are tolerant of stress-induced premature senescence remains unknown. Here, we show that primary mouse embryonic fibroblasts derived from Nampt-overexpressing transgenic mice (Nampt Tg-MEF cells) possess resistance against stress-induced premature senescence in vitro. We found that higher oxidative or endoplasmic reticulum (ER) stress is required to induce premature senescence in Nampt Tg-MEF cells compared to wild-type cells. Moreover, we found that Nampt Tg-MEF cells show acute expression of unfolded protein response (UPR)-related genes, which in turn would have helped to restore proteostasis and avoid cellular senescence. Our results demonstrate that NAMPT/NAD+ axis functions to protect cells not only from replicative senescence, but also from stress-induced premature senescence in vitro. We anticipate that in vivo activation of NAMPT activity or increment of NAD+ would protect tissues from the accumulation of premature senescent cells, thereby maintaining healthy aging.
Occurrences of allergenicity to banana pathogenesis-related-10 (PR10) protein variants

Suhaimi AH, Rajendram A, Khaidizar FD, Mir P, Pulido-Lucas E, Quirce S, et al.

Food Funct, 2024 Nov 14.
PMID: 39539124 DOI: 10.1039/d4fo03301a

Pathogenesis-related-10 (PR10) proteins play significant roles in plant defence against biotic and abiotic stresses. Recently, two banana PR10 proteins (MaPR10-BeB5 and MaPR10-GNA5) were characterised and shown to exhibit antifungal properties against Aspergillus fumigatus in vitro. In rice, transgenic overexpression of PR10 proteins conferred resistance to pathogen infection and drought tolerance without affecting productivity, highlighting their potential for agricultural applications. However, PR10 proteins also include the Bet v 1-like family of allergens implicated in pollen food allergy syndromes, raising concerns about potential adverse effects on human health. In this study, we evaluated the allergenic potential of the recently isolated banana PR10 proteins. We first predicted the presence of IgE epitopes of the Bet v 1 allergen family in the deduced PR10 peptide sequences in silico. We then predicted the structures of four human IgE scFv protein sequences and three plant PR10 protein sequences. Based on the quality of the predicted structures, one IgE scFv protein structure was selected for docking with the three plant PR10 proteins. We confirmed the docking results with immunoblot analysis performed using recombinant MaPR10-BeB5 and MaPR10-GNA5 proteins against the sera of banana-allergic patients. Our experimental results substantiated the notion that both protein variants are potentially allergenic since these proteins were recognised by 26.6% of banana-allergic patients with broad PR10 protein recognition. We caution that the allergenic potential of MaPR10 proteins should be carefully considered before implementing transgenic overexpression strategies to improve crops, with a suggestion to limit their expression to non-edible plant tissues.